Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index.

Autor: Lyon RP; Department of Chemistry, Seattle Genetics, Bothell, Washington, USA., Bovee TD; Department of Chemistry, Seattle Genetics, Bothell, Washington, USA., Doronina SO; Department of Chemistry, Seattle Genetics, Bothell, Washington, USA., Burke PJ; Department of Chemistry, Seattle Genetics, Bothell, Washington, USA., Hunter JH; Department of Chemistry, Seattle Genetics, Bothell, Washington, USA., Neff-LaFord HD; Department of Pharmacology and Toxicology, Seattle Genetics, Bothell, Washington, USA., Jonas M; Department of Translational Research, Seattle Genetics, Bothell, Washington, USA., Anderson ME; Department of Preclinical Research, Seattle Genetics, Bothell, Washington, USA., Setter JR; Department of Chemistry, Seattle Genetics, Bothell, Washington, USA., Senter PD; Department of Chemistry, Seattle Genetics, Bothell, Washington, USA.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2015 Jul; Vol. 33 (7), pp. 733-5. Date of Electronic Publication: 2015 Jun 15.
DOI: 10.1038/nbt.3212
Abstrakt: The in vitro potency of antibody-drug conjugates (ADCs) increases with the drug-to-antibody ratio (DAR); however, ADC plasma clearance also increases with DAR, reducing exposure and in vivo efficacy. Here we show that accelerated clearance arises from ADC hydrophobicity, which can be modulated through drug-linker design. We exemplify this using hydrophilic auristatin drug linkers and PEGylated ADCs that yield uniform, high-DAR ADCs with superior in vivo performance.
Databáze: MEDLINE
Externí odkaz: